Many disease conditions or injuries of the body require the repair or replacement of damaged tissues and/or structures, but the body itself may not be able to replace or repair the tissue and/or structures satisfactorily or within an appropriate time scale. Accordingly, many methods of disease or injury treatment involve augmenting the body's natural repair mechanisms and often rely on the use of implantable biological scaffolds or prostheses. Tissue engineering attempts to create three-dimensional tissue structures on which cells and other biomolecules can be incorporated. These structures or scaffolds guide the organization, growth and differentiation of cells in the process of forming functional tissue by providing physico-chemical cues.
For example, degenerative joint diseases such as osteoarthritis remain a source of significant pain and disability, resulting in an economic burden of over 40 billion dollars per year to the United States. Present treatment options for osteoarthritis are limited, and surgical management generally involves replacement of the joint with a metal and polyethylene prosthesis. The short life span and loading tolerance of joint replacement makes this treatment unacceptable for young, potentially active individuals. The treatment of synovial joints using tissue engineered grafts shows tremendous promise but its application has been limited to the treatment of small cartilage defects in the knee joint.
Further, articular cartilage is avascular, aneural, and has limited capacity for self-repair. Particularly, articular cartilage is a thin layer of soft connective tissue (0.5-5 mm thick) that covers the articulating surfaces of long bones in synovial joints. The principal function of articular cartilage is to redistribute applied loads and to provide a flow friction-bearing surface to facilitate movement within these joints. Damage to this connective tissue in joints results in significant pain and morbidity, and currently, there are few options available for treatment. Some treatment options include lavage, debridement, microfracture, and autologous and/or allogeneic osteochondral/chondral grafts (reviewed in Hunziker (2002) Osteoarthritis Cartilage 10:432-463.
The success rates from these treatment options vary greatly, and some show promise. However, in many of the studies, the results suggest fibrous tissue formation, apoptosis, and further cartilage degeneration nonetheless occur (Furukawa et al. (1980) J Bone Joint Surg Am 62:79-89; Kim et al. (1991) J Bone Joint Surg Am 73:1301-1315; Shapiro et al. (1993) J Bone Joint Surg Am 75:532-553; Nehrer et al. (1999) Clin Orthop Relat Res 365:149-162; Tew et al. (2000) Arthritis Rheum 43:215-225; Mitchell and Shephard (2004) Clin Orthop Relat Res 423:3-6. Autologous chondrocyte transplants studies have also shown an inability to produce hyaline cartilage repair tissue, specifically over long time periods Brittberg et al. (1996) Clin Orthop Relat Res 326:270-283; Brittberg (1999) Clin Orthop Relat Res 367(Suppl):S147-155; Nehrer et al. (1999) Clin Orthop Relat Res 365:149-162; Breinan et al. (2001) J Orthop Relat Res 19:482-492, and even though some clinical studies have shown some promising results Brittberg et al. (1994) N Engl J Med 331:889-895; Breinan et al. (1997) J Bone Joint Surg Am 79:1439-1451; Minas and Nehrer (1997) Orthopedics 20:525-538; Gillogly et al. (1998) J Orthop Sports Phys Ther 28:241-251, as with the other treatment options, randomized, controlled trials are needed to truly ascertain the efficacy of these procedures. Given the success rate to date of current cartilage remodeling, repair, regrowth, and/or regeneration treatment options, combined with the burgeoning economic burden cartilage pathology and osteoarthritis has on society (Jackson et al. (2001) Clin Orthop Relat Res 391(Suppl):S14-25), novel tissue engineering approaches are needed to establish improved options for the treatment of cartilage defects and osteoarthritis, among other maladies.
In recent years, the identification of mesenchymal stem cells has led to advances in tissue regrowth and differentiation. Such cells are pluripotent cells found in bone marrow and periosteum, capable of differentiating into various mesenchymal or connective tissues. For example, such bone-marrow derived stem cells can be induced to develop into myocytes upon exposure to agents such as 5-azacytidine (Wakitani et al. (1995) Muscle Nerve, 18(12), 1417-26). It has been suggested that such cells are useful for repair of tissues such as cartilage, fat, and bone (see, e.g., U.S. Pat. Nos. 5,908,784, 5,906,934, 5,827,740, 5,827,735), and that they also have applications through genetic modification (see, e.g., U.S. Pat. No. 5,591,625). While the identification of such cells has led to advances in tissue regrowth and differentiation, the use of such cells is hampered by several technical hurdles. One drawback to the use of such cells is that they are very rare (representing as few as 1/2,000,000 cells), making any process for obtaining and isolating them difficult and costly. Additionally, bone marrow harvest is universally painful to the donor. Moreover, such cells are difficult to culture without inducing differentiation, unless specifically screened sera lots are used, adding further cost and labor to the use of such stem cells. Thus, there is a need for a more readily available source for pluripotent stem cells, particularly cells that can be cultured without the requirement for costly prescreening of culture materials.
Other advances in tissue engineering have shown that cells can be grown in specially-defined cultures to produce three-dimensional structures. Spatial definition typically is achieved by using various acellular fiber scaffolds or matrices to support and guide cell growth and differentiation. While this technique is still in its infancy, experiments in animal models have demonstrated that it is possible to employ various acellular fiber scaffold materials to regenerate whole tissues (see, e.g., Probst et al. (2000) BJU Int., 85(3), 362-367). While artificial fiber scaffolds have been developed, these can prove toxic either to cells or to patients when used in vivo, or do not provide adequate mechanical support required for tissue repair. Accordingly, there remains a need for a scaffold material suitable for use as a substrate in culturing and growing populations of cells, wherein the matrix, cell combination is tailored specifically for replacement of a target tissue. Ultimately, this replacement tissue will serve to substantially function as the native tissue it seeks to replace.
Accordingly, the presently disclosed subject matter addresses needs in the art for improved methods for producing improved tissue engineered implantable compositions. This and other needs are addressed in whole or in part by the presently disclosed subject matter.